SK channels and NMDA receptors form a Ca2+-mediated feedback loop in dendritic spines

Abstract

Small-conductance Ca²⁺-activated K⁺ channels (SK channels) influence the induction of synaptic plasticity at hippocampal CA3–CA1 synapses. We find that in mice, SK channels are localized to dendritic spines, and their activity reduces the amplitude of evoked synaptic potentials in an NMDA receptor (NMDAR)-dependent manner. Using combined two-photon laser scanning microscopy and two-photon laser uncaging of glutamate, we show that SK channels regulate NMDAR-dependent Ca²⁺ influx within individual spines. SK channels are tightly coupled to synaptically activated Ca²⁺ sources, and their activity reduces the amplitude of NMDAR-dependent Ca²⁺ transients. These effects are mediated by a feedback loop within the spine head; during an excitatory postsynaptic potential (EPSP), Ca²⁺ influx opens SK channels that provide a local shunting current to reduce the EPSP and promote rapid Mg²⁺ block of the NMDAR. Thus, blocking SK channels facilitates the induction of long-term potentiation by enhancing NMDAR-dependent Ca²⁺ signals within dendritic spines.